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000165289 037__ $$aDZNE-2022-01582
000165289 041__ $$aEnglish
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000165289 1001_ $$0P:(DE-2719)9000981$$aDash, Banaja$$b0$$udzne
000165289 245__ $$aDownstream Effects of Mutations in SOD1 and TARDBP Converge on Gene Expression Impairment in Patient-Derived Motor Neurons.
000165289 260__ $$aBasel$$bMolecular Diversity Preservation International$$c2022
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000165289 520__ $$aAmyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease marked by death of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Despite extensive research, the reason for neurodegeneration is still not understood. To generate novel hypotheses of putative underlying molecular mechanisms, we used human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs) from SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls to perform high-throughput RNA-sequencing (RNA-Seq). An integrated bioinformatics approach was employed to identify differentially expressed genes (DEGs) and key pathways underlying these familial forms of the disease (fALS). In TDP43-ALS, we found dysregulation of transcripts encoding components of the transcriptional machinery and transcripts involved in splicing regulation were particularly affected. In contrast, less is known about the role of SOD1 in RNA metabolism in motor neurons. Here, we found that many transcripts relevant for mitochondrial function were specifically altered in SOD1-ALS, indicating that transcriptional signatures and expression patterns can vary significantly depending on the causal gene that is mutated. Surprisingly, however, we identified a clear downregulation of genes involved in protein translation in SOD1-ALS suggesting that ALS-causing SOD1 mutations shift cellular RNA abundance profiles to cause neural dysfunction. Altogether, we provided here an extensive profiling of mRNA expression in two ALS models at the cellular level, corroborating the major role of RNA metabolism and gene expression as a common pathomechanism in ALS.
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000165289 650_7 $$2Other$$aRNA sequencing (RNA-Seq)
000165289 650_7 $$2Other$$aamyotrophic lateral sclerosis (ALS)
000165289 650_7 $$2Other$$adifferentially expressed genes (DEG)
000165289 650_7 $$2Other$$ahuman induced pluripotent stem cells (iPSC)
000165289 650_7 $$2Other$$amotor neurons (MN)
000165289 650_7 $$2Other$$aprotein-protein interaction (PPI)
000165289 650_7 $$2NLM Chemicals$$aDNA-Binding Proteins
000165289 650_7 $$2NLM Chemicals$$aSOD1 protein, human
000165289 650_7 $$2NLM Chemicals$$aTARDBP protein, human
000165289 650_7 $$063231-63-0$$2NLM Chemicals$$aRNA
000165289 650_7 $$0EC 1.15.1.1$$2NLM Chemicals$$aSuperoxide Dismutase-1
000165289 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000165289 650_2 $$2MeSH$$aDNA-Binding Proteins: genetics
000165289 650_2 $$2MeSH$$aDNA-Binding Proteins: metabolism
000165289 650_2 $$2MeSH$$aGene Expression
000165289 650_2 $$2MeSH$$aHumans
000165289 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000165289 650_2 $$2MeSH$$aMotor Neurons: metabolism
000165289 650_2 $$2MeSH$$aMutation
000165289 650_2 $$2MeSH$$aNeurodegenerative Diseases: metabolism
000165289 650_2 $$2MeSH$$aRNA: metabolism
000165289 650_2 $$2MeSH$$aSuperoxide Dismutase-1: genetics
000165289 7001_ $$0P:(DE-2719)9001054$$aFreischmidt, Axel$$b1$$udzne
000165289 7001_ $$0P:(DE-2719)9000455$$aWeishaupt, Jochen H$$b2$$udzne
000165289 7001_ $$0P:(DE-2719)2811732$$aHermann, Andreas$$b3$$eLast author$$udzne
000165289 770__ $$aNeurological Diseases: A Molecular Genetic Perspective
000165289 773__ $$0PERI:(DE-600)2019364-6$$a10.3390/ijms23179652$$gVol. 23, no. 17, p. 9652 -$$n17$$p9652$$tInternational journal of molecular sciences$$v23$$x1422-0067$$y2022
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